Delirium severity and outcomes of critically ill COVID-19 patients

Objective To investigate the impact of delirium severity in critically ill COVID-19 patients and its association with outcomes. Methods This prospective cohort study was performed in two tertiary intensive care units in Rio de Janeiro, Brazil. COVID-19 patients were evaluated daily during the first 7 days of intensive care unit stay using the Richmond Agitation Sedation Scale, Confusion Assessment Method for Intensive Care Unit (CAM-ICU) and Confusion Method Assessment for Intensive Care Unit-7 (CAM-ICU-7). Delirium severity was correlated with outcomes and one-year mortality. Results Among the 277 COVID-19 patients included, delirium occurred in 101 (36.5%) during the first 7 days of intensive care unit stay, and it was associated with a higher length of intensive care unit stay in days (IQR 13 [7 - 25] versus 6 [4 - 12]; p < 0.001), higher hospital mortality (25.74% versus 5.11%; p < 0.001) and additional higher one-year mortality (5.3% versus 0.6%, p < 0.001). Delirium was classified by CAM-ICU-7 in terms of severity, and higher scores were associated with higher in-hospital mortality (17.86% versus 34.38% versus 38.46%, 95%CI, p value < 0.001). Severe delirium was associated with a higher risk of progression to coma (OR 7.1; 95%CI 1.9 - 31.0; p = 0.005) and to mechanical ventilation (OR 11.09; 95%CI 2.8 - 58.5; p = 0.002) in the multivariate analysis, adjusted by severity and frailty. Conclusion In patients admitted with COVID-19 in the intensive care unit, delirium was an independent risk factor for the worst prognosis, including mortality. The delirium severity assessed by the CAM-ICU-7 during the first week in the intensive care unit was associated with poor outcomes, including progression to coma and to mechanical ventilation.

duration of delirium are also independently associated with higher mortality and morbidity in the ICU. (15,16)lthough there are many studies assessing the incidence and impact of delirium in critically ill COVID-19 patients, (14,17,18) few have focused on delirium severity in this setting. (5,13,19)Therefore, the aim of the present study is to investigate the impact of delirium severity in critically ill COVID-19 patients and its association with the main outcomes.

Study design and participants
We conducted a prospective cohort study in the ICUs of two tertiary hospitals in Rio de Janeiro, Brazil, between May 1st and 31st August 2020.All adult patients admitted with clinical and radiological suspicion of COVID-19 were evaluated daily during the first seven days of ICU stay.Subsequently, according to the results of the polymerase chain reaction (PCR) tests, we excluded and removed patients with negative results from the analysis.Only those with a confirmed diagnosis of coronavirus infection by a positive PCR for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in nasopharynx and oropharynx swabs were included in the study.Exclusion criteria were inability to collaborate with the delirium assessment (deafness, amaurosis, previous severe dementia or other severe cognitive impairment), persistence of coma (defined by Richmond Agitation-Sedation Scale [RASS] -4 and -5 in first week of admission) and a previous decision of palliative care.Patients who could not be evaluated in the first 24 hours of ICU stay were also excluded.A flowchart of patient inclusion is provided in figure 1.
The study was approved by the Research Ethics Committee (Instituto D'Or de Pesquisa e Ensino, CAAE 17079119.7.0000.5249),with a waiver in the application of informed consent due to the observational nature of the study.

Data collection
Demographic and clinical data were collected prospectively from the charts, electronic records or patient proxies, including the date of symptom onset and presence of comorbidities (dementia or cognitive deficit, diabetes mellitus, chronic obstructive pulmonary disease, alcoholism, systemic arterial hypertension, heart failure, immunosuppression or active cancer, chronic kidney disease or obesity).The E-predeliric, (20) Charlson Comorbidities Index (CCI), (21) modified Frailty Index (m-FI) (22) and Simplified Acute Physiology Score 3 (SAPS 3) (23) on admission were calculated and recorded.During the first seven days of ICU stay, the RASS, (24) Confusion Assessment Method for the ICU (CAM-ICU) (25) and Confusion Assessment Method for the ICU-7 (CAM-ICU-7, a validated delirium severity 7-point scale that graduates and sums each component of the CAM-ICU); (26) the use of systemic corticosteroids, sedatives, and antipsychotics; and laboratory data and Sequential Organ Failures Assessment (SOFA) (27) were checked and recorded daily.
Every morning during the first seven days of ICU stays, a systematic evaluation of sedation, coma and delirium was performed by three senior intensivists, most of the time by the same intensivists, using the RASS scale, the CAM-ICU and the CAM-ICU-7,.
Assessment of delirium was only possible in patients with RASS scores greater than RASS-3.Patients with RASS-4 and RASS-5 scores were categorized as comas.Patients who had delirium on at least one of the days of analysis were considered patients in the group with delirium, and patients who did not have delirium on any of the days analyzed were considered without delirium.Patients who remained in a coma for the entire time of the analysis were excluded.The CAM-ICU-7 mean was calculated by the arithmetic mean of the days that this patient was assessed for delirium during the seven days of the analysis.

Outcomes
Our primary outcomes were delirium incidence and severity (measured by the CAM-ICU-7 score) and its association with hospital mortality rates.In addition, we evaluated secondary outcomes: progression to coma and to MV, ICU LOS and one-year mortality in survivors after discharge (these last data were extracted from the governmental database of Corregedoria Geral do Tribunal de Justiça do Rio de Janeiro -TJRJ).We emphasize that nonclinical factors had an impact on our length of hospital stay, such as respiratory isolation time and lack of availability of hospital ICU and non-ICU beds to receive these patients.

Statistical analysis
Data are presented as medians with interquartile ranges (IQRs) for continuous variables and absolute values and percentages for categorical variables.As appropriate, categorical variables were compared using the chi squared or Fisher's exact test, and continuous variables were compared using the Kruskal-Wallis or Mann-Whitney U test.
Delirium severity was described by calculating the CAM-ICU-7 means in the first seven days of ICU stay and stratified accordingly with strata as described in the original article (< 3: mild delirium; 3 -5.99:moderate delirium and 6 -7: severe delirium). (26)The length of stay in the ICU and in the hospital was analyzed using the Fine-Gray subdistribution hazard competing risk model. (28,29)The hazard ratio of discharge chance from the hospital and ICU was calculated by comparing delirium and nondelirium patients with the median time to discharge of the total sample.
The association of delirium severity with outcomes was explored using a univariate analysis by estimating the risk ratios.After univariate analysis, variables that presented a p < 0.25 were entered in the multivariate analysis to correlate delirium with the primary and secondary outcomes.Multivariable adjusted logistic regression models adjusted by SAPS 3 and frailty were used to estimate the odds ratios (for mortality, late mortality, progression to coma and to MV) and hazard ratios (chance of hospital and ICU discharge) and 95% confidence intervals (95%CI).All tests were two-sided, and statistical significance was defined at a level of 95%CI, with a p value < 0.05.All analyses were performed with R software version 4.2.1 using the final fit and survival packages.
The in-hospital mortality rates in the delirium and non delirium groups were 25.74% versus 5.11%, respectively (p < 0.001).The additional one-year mortality of patients who were discharged alive from the hospital was 5.3% in delirium versus 0.6% in non delirium patients, p < 0.001 (Table 2).Patients were at increased risk of requiring invasive MV after developing delirium (OR 51.35 [95%CI  11.65 -226.35];p < 0.001) and had a lower chance of discharge from the ICU (HR 0.54 [95%CI 0.40 -0.71]; p < 0.001)) than those without delirium.In multivariate analysis, delirium was also independently associated with mortality OR 3.04 (95%CI 1.26 -7.36); p = 0.014 (Table 3).
Delirium was classified according to the CAM-ICU-7 mean in three levels of severity: mild, moderate, and severe.A higher level of delirium was associated with a higher frailty status prevalence (41.1% versus 71.9% versus 77%; p < 0.001) and higher in-hospital mortality (17.9% versus 34.4% versus 38.5%; p < 0.001) (Table 4).

DISCUSSION
In our prospective cohort, the incidence of delirium was high (36.5%),and it was associated with increased inhospital mortality, increased ICU and hospital LOS and a higher use of MV, even when adjusted for other severity scores (SAPS 3 and frailty).
The delirium occurrence was higher when compared to a similar ICU population without COVID-19. (15,16,30)33) Our cohort described a very low one-year mortality of patients with delirium after discharge (5.3%); nevertheless, it was 8 times higher than late mortality in non-COVID patients.Despite few studies describing late mortality in patients with COVID-19, our result was similar to other recent observational studies that found only 1% one-year mortality in COVID-19 survivors. (34)Although delirium occurrence in non-COVID-19 patients has been associated with a higher 1-year mortality, (35,36) late survival to COVID-19 is closely associated with comorbidities and functional status. (37)In our cohort, delirium survivors were less frail (m-FI: 27. ; p < 0.001) than nonsurvivors.We also described the correlation between delirium severity (according to the mean CAM-ICU-7 assessment) and outcomes.
There are only a few studies comparing delirium severity and outcomes in critically ill COVID-19 patients. (38)Only one study described an increase in mortality in

Measures of effect (95%CI) p value Measures of effect (95%CI) p value
Chance of hospital discharge HR 0.6 (0.  coma patients but did not describe subgroups of delirium severity. (37)Our study described that the mortality of patients with moderate to severe delirium was nearly twice that observed in mild delirium (respectively 17.9% and 34.4% versus 38.5%; p < 0.001).Similar to rapid reverse delirium, mild delirium represents a lower risk of death. (5)n our cohort, severe delirium was also associated with a high amount of resources used (MV or length of stay).Monitoring delirium severity can identify high-risk patients and resource allocation.The imbalance between supply and demand for medical resources during the pandemic highlights the importance of projecting future demands in the ICU regarding delirium severity.
Delirium diagnosis and monitoring was also a challenge during the COVID-19 pandemic.Spread barriers need to be adopted, and the main emphasis has been placed on organizational barriers in the COVID-19 population.In our sample, E-predeliric had a discriminative performance similar to that of patients without COVID-19, with an issue hindering bedside delirium screening.Our performance of the E-predelic score in delirium prediction had an area under the ROC curve of 0.783, p < 0.001, which is very similar to that described in non-COVID-19 patients. (20,38)nderstanding delirium patterns and characteristics can help to select appropriate screening tools and preventive measures for future conditions.Our study has many strengths, including the prospective design, the bedside data collection (not chartbased method), the size of our sample, the multivariate analysis adjusting for possible confounders and mainly the assessment of delirium severity and its prognosis in this population.There are few studies describing outcomes and late mortality in patients with delirium and COVID-19, and the CAM-ICU-7 has been underexplored in this population.
While effective pharmacological therapies for delirium are not yet available, (18) our data emphasize delirium as a predictor of poor outcomes in the ICU population admitted with COVID-19 and the importance of implementing a screening protocol as well as monitoring the severity of delirium.
However, some limitations need to be highlighted.First, it is worth noting that our analysis focused only on the first week of ICU stay, which may have underestimated the incidence of delirium.However, it is important to recognize that delirium is more likely to occur during the initial days of admission. (5)Therefore, early monitoring for delirium remains critical in guiding decision-making during ICU treatment.Second, as we performed this study at the beginning of the first wave of the pandemic and there was a large concern about the virus spreading, we limited patient assessment to one visit a day, which may also have reduced our detection of delirium.Third, the sample we analyzed may not represent the entire population, as many patients were unable to be evaluated using the CAM-ICU or CAM-ICU-7.This could result in a potentially less severe patient population.A significant number of patients needed MV and deep sedation due to severe hypoxemia.Additionally, many patients require benzodiazepines for sedation due to a shortage of short-acting drugs. (39,40)ourth, the lack of details regarding corticosteroid use in our study population could represent a confounding bias.It is important to note that our study was conducted in the early stages of the pandemic when there was still controversy and concern about the use of corticosteroids, especially in advanced infection cases.Finally, we evaluated only late mortality, and we did not evaluate other late outcomes, such as the prevalence of functional decline or the presence of posttraumatic stress syndrome.

CONCLUSION
The incidence of delirium was high in COVID-19 patients.Delirium was an independent risk factor for the worst prognosis, including mortality during hospitalization, but had a slight impact on 1-year mortality.
Our study emphasizes the applicability of the CAM-ICU-7 scale in the COVID-19 intensive care unit population and reinforces the importance of graduating delirium and its correlation with worse outcomes.The delirium severity assessed by the CAM-ICU-7 during the first week in the intensive care unit was associated with poor outcomes, including evolution to coma and to mechanical ventilation.

Figure 2 -
Figure 2 -Comparison of the three median strata of delirium severity with the following outcomes (in odds ratio or hazard ratio, 95% confidence intervals): mortality, late mortality, chance (in percentage) of intensive care unit discharge, chance (in percentage) of hospital discharge, chance of evolution to coma (in percentage) and chance (in percentage) of evolution to invasive mechanical ventilation.(A) Confusion Assessment Method for the Intensive Care Unit-7 mean < 3; (B) Confusion Assessment Method for the Intensive Care Unit-7 mean between 3 -5.99;(C) Confusion Assessment Method for the Intensive Care Unit-7 mean > 6.. ICU -intensive care unit.

Table 1 -
Clinical and demographic variables of the population with and without delirium

Table 2 -
Clinical outcomes of the population with and without delirium ICU -intensive care unit.Results expressed as the median (interquartile range)

Table 3 -
Delirium and outcomes in multivariate analysis

Table 4 -
Clinical scores and patient outcomes relative to the stratification of delirium severity by Confusion Assessment Method for Intensive Care Unit-7 CAM-ICU-7 -Confusion Assessment Method for the Intensive Care Unit 7; SAPS 3 -Simplified Acute Physiology Score 3; m-FI -modified Frailty Index; ICU -intensive care unit; MV -mechanical ventilation.The results are expressed as the median (interquartile range) or n (%).

Table 5 -
Outcomes in delirium patients classified by Confusion Assessment Method for Intensive Care Unit-7 mean in multivariate analysis